Researchers make glioblastoma cells visible to immune cells that attack them

Scientists at Washington University School of Medicine in St. Louis use cell-based research to force glioblastoma cells to display immune system targets, making them visible to immune cells and potentially susceptible to new immunotherapies. It was announced that there is. This strategy involves a combination of two drugs already approved by the FDA to treat different cancers.

This study is published in an online journal natural genetics.

“We show that there is a way to induce the production of immunotherapy targets in patients whose tumors do not naturally produce them,” said co-authors Ting Wang, Ph.D., Sanford C. and Cullen P. said Dr. Lowentoyle, professor emeritus of medicine and director. in the Department of Genetics at WashU Medicine. “In other words, if we don't have a target, we can create a target. This is a very new way to design targeted and precision therapies for cancer. We hope to be able to move it into clinical trials in the near future.” Combining immunotherapy with this strategy can provide a new treatment approach for patients with extremely difficult-to-treat cancers.”

To create immune targets on cancer cells, Wang focused on portions of DNA within the genome known as transposable elements. According to Wang, in recent years, metastatic elements have emerged as a double-edged sword in cancer. His research shows that metastatic elements play a role in driving tumor development, even though they present vulnerabilities that can be exploited to generate new cancer treatment strategies. Masu.

In this study, Wang's team took advantage of the fact that transposable elements can naturally cause large amounts of random proteins to be produced that are unique to tumors and not present in normal cells. These rare proteins, called tumor antigens or neoantigens, are potential targets for immunotherapies such as checkpoint inhibitors, antibodies, vaccines, and recombinant T-cell therapies.

Still, some tumors, such as glioblastoma, have few immune targets naturally produced by transposable elements. To address this, Dr. Wang and his colleagues, including co-senior author Albert H. Kim, M.D., August A. We demonstrated a method to generate immune system targets for glioblastoma. cells that normally lack them.

The researchers used a combination of two drugs that affect the so-called epigenome, which controls which genes are turned on and to what extent in cells. Treatment with two epigenetic drugs causes the densely packed DNA molecules of glioblastoma cells to spread out and start producing rare proteins that transposable elements can use to target cancer cells. The two drugs are decitabine, which is approved to treat myelodysplastic syndromes, a group of blood cancers. Panobinostat is approved for multiple myeloma, a cancer of white blood cells.

Before studying this strategy in humans, researchers are looking for ways to target epigenetic therapy so that only tumor cells are induced to produce neoantigens. In the new study, researchers warned that normal cells also generate targets when exposed to the two drugs. Although normal cells did not produce as many neoantigens as glioblastoma cells, there is a risk of unwanted side effects if normal cells also produce these targets, Wang and Kim said.

In ongoing research, Wang and Kim are investigating how to use CRISPR molecular editing technology to direct specific parts of a cancer cell's genome to generate the same neoantigens from transposable elements that are common throughout humanity. Masu. Such a strategy could give many patients' tumors (even different types of cancer) the same target that would respond to the same immunotherapy, while sparing healthy cells. There are multiple ways to target these common targets, including checkpoint inhibitors, vaccines, engineered antibodies, and engineered T cells.

“Immunotherapy has revolutionized the treatment of some specific cancers, such as melanoma,” said John, who treats patients at the Siteman Cancer Center, based at Barnes-Jewish Hospital and WashU Medicine. said Kim, who is also the director of the Brain Tumor Center. “The progression of glioblastoma is slow by comparison, as this tumor is highly resistant to modern treatment strategies. However, recent advances in immunotherapy and epigenetic therapy, when used in combination, We're hopeful that we're on the right track because we can.'' Similar transformational changes are being seen in the treatment of glioblastoma. ”